Aging is the accumulation of many events or processes that affect several biological systems. The neuroendocrine theory of aging has broad application because the hypothalamus contains "command cells" or centers that perform homeostatic or integrative functions for many systems that show decreased function with aging. Neurons in the hypothalamus secrete peptides or biogenic amines that profoundly influence pituitary hormones. In turn, pituitary hormones or the products of their target endocrine glands can affect brain neurons, and these effects may become detrimental with aging. The tuberoinfundibular dopamine (TIDA) neurons in the hypothalamus release dopamine (DA), which tonically inhibits prolactin (PRL) secretion. PRL, in turn, stimulates the TIDA neurons. The goal of this research is to establish whether elevated PRL damages or adversely affects these neurons in aging rats, and the molecular or cellular mechanisms by which this occurs. The incidence of pituitary tumors in humans, of which prolactinomas are the most common, may be as high as 28% based on findings at autopsy. Therefore a demonstration that elevated PRL permanently alters gene expression and neuronal function in TIDA neurons may have clinical relevance. Four in vivo studies and one neuronal cell culture study form the basis for this proposal. All of the studies focus on tyrosine hydroxylase (TH) the rat-limiting enzyme for the synthesis of DA in the TIDA zona incerta (ZI) and substantia nigra (SN) neurons. In the first study, baseline measurements in TH gene expression and catalytic activity at various ages in the female rat in these three distinct neuronal systems will be made. Next, PRL secretion will be tonically inhibited and neuronal function compared to controls which naturally have much higher PRL levels. Thirdly, the converse will be done, such that PRL levels will be evaluated for the first year of life, in an attempt to hasten changes in TIDA neuronal function. Fourthly, progesterone and estradiol, whose receptors are found in TIDA neurons, will be elevated during the postpubertal life of the rat, and neuronal function assessed. Finally, a long-term culture of TIDA neurons will be used to ascertain the direct effects of PRL, progesterone and estrogen, all thought to have a role in the aging process of DA neurons, on TH. Since debilitating diseases occur with age as a result of decline in function of DA neurons, it is important to learn what regulates these neurons.